Gravitational waves from inspiralling compact binaries: Parameter estimation using second-post-Newtonian waveforms

The parameters of inspiralling compact binaries can be estimated using matched filtering of gravitational-waveform templates against the output of laser-interferometric gravitational-wave detectors. Using a recently calculated formula, accurate to second post-Newtonian (2PN) order [order $(v/c)^4$, where $v$ is the orbital velocity], for the frequency sweep ($dF/dt$) induced by gravitational radiation damping, we study the statistical errors in the determination of such source parameters as the ``chirp mass'' $\cal M$, reduced mass $\mu$, and spin parameters $\beta$ and $\sigma$ (related to spin-orbit and spin-spin effects, respectively). We find that previous results using template phasing accurate to 1.5PN order actually underestimated the errors in $\cal M$, $\mu$, and $\beta$. For two inspiralling neutron stars, the measurement errors increase by less than 16 percent.Comment: 14 pages, ReVTe

Renal cyst growth is attenuated by a combination treatment of tolvaptan and pioglitazone, while pioglitazone treatment alone is not effective

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders, characterized by the progressive formation of fluid-filled cysts. Tolvaptan is an approved drug for ADPKD patients, but is also associated with multiple side effects. The peroxisome proliferator-activator receptor gamma (PPAR gamma) agonist pioglitazone slows disease progression in the PCK rat model for PKD. Here, we tested whether a combination treatment of relevant doses of tolvaptan and pioglitazone leads to improved efficacy in an adult-onset PKD mouse model. Tolvaptan indeed slowed PKD progression, but the combination treatment was not more effective than tolvaptan alone. In addition, although pioglitazone raised plasma levels of its surrogate drug marker adiponectin, the drug unexpectedly failed to slow PKD progression. The pioglitazone target PPAR. was expressed at surprisingly low levels in mouse, rat and human kidneys. Other pioglitazone targets were more abundantly expressed, but this pattern was comparable across various species. The data suggest that several potential pharmacokinetic and pharmacodynamic (PK/PD) differences between different species may underlie whether or not pioglitazone is able to slow PKD progression. The ongoing phase II clinical trial with low-dose pioglitazone treatment (NCT02697617) will show whether pioglitazone is a suitable drug candidate for ADPKD treatment.Functional Genomics of Systemic Disorder

Gravitational radiation from a particle in circular orbit around a black hole. V. Black-hole absorption and tail corrections

A particle of mass $\mu$ moves on a circular orbit of a nonrotating black hole of mass $M$. Under the restrictions $\mu/M \ll 1$ and $v \ll 1$, where $v$ is the orbital velocity, we consider the gravitational waves emitted by such a binary system. We calculate $\dot{E}$, the rate at which the gravitational waves remove energy from the system. The total energy loss is given by $\dot{E} = \dot{E}^\infty + \dot{E}^H$, where $\dot{E}^\infty$ denotes that part of the gravitational-wave energy which is carried off to infinity, while $\dot{E}^H$ denotes the part which is absorbed by the black hole. We show that the black-hole absorption is a small effect: $\dot{E}^H/\dot{E} \simeq v^8$. We also compare the wave generation formalism which derives from perturbation theory to the post-Newtonian formalism of Blanchet and Damour. Among other things we consider the corrections to the asymptotic gravitational-wave field which are due to wave-propagation (tail) effects.Comment: ReVTeX, 17 page

Gravitational waves from inspiralling compact binaries: Energy loss and waveform to second--post-Newtonian order

Gravitational waves generated by inspiralling compact binaries are investigated to the second--post-Newtonian (2PN) approximation of general relativity. Using a recently developed 2PN-accurate wave generation formalism, we compute the gravitational waveform and associated energy loss rate from a binary system of point-masses moving on a quasi-circular orbit. The crucial new input is our computation of the 2PN-accurate ``source'' quadrupole moment of the binary. Tails in both the waveform and energy loss rate at infinity are explicitly computed. Gravitational radiation reaction effects on the orbital frequency and phase of the binary are deduced from the energy loss. In the limiting case of a very small mass ratio between the two bodies we recover the results obtained by black hole perturbation methods. We find that finite mass ratio effects are very significant as they increase the 2PN contribution to the phase by up to 52\%. The results of this paper should be of use when deciphering the signals observed by the future LIGO/VIRGO network of gravitational-wave detectors.Comment: 43 pages, LaTeX-ReVTeX, no figures

Human conjunctiva organoids to study ocular surface homeostasis and disease

The conjunctival epithelium covering the eye contains two main cell types: mucus-producing goblet cells and water-secreting keratinocytes, which present mucins on their apical surface. Here, we describe long-term expanding organoids and air-liquid interface representing mouse and human conjunctiva. A single-cell RNA expression atlas of primary and cultured human conjunctiva reveals that keratinocytes express multiple antimicrobial peptides and identifies conjunctival tuft cells. IL-4/-13 exposure increases goblet and tuft cell differentiation and drastically modifies the conjunctiva secretome. Human NGFR+ basal cells are identified as bipotent conjunctiva stem cells. Conjunctival cultures can be infected by herpes simplex virus 1 (HSV1), human adenovirus 8 (hAdV8), and SARS-CoV-2. HSV1 infection was reversed by acyclovir addition, whereas hAdV8 infection, which lacks an approved drug therapy, was inhibited by cidofovir. We document transcriptional programs induced by HSV1 and hAdV8. Finally, conjunctival organoids can be transplanted. Together, human conjunctiva organoid cultures enable the study of conjunctival (patho)-physiology.</p

Neighborhood deprivation and risk of mortality among men with prostate cancer: Findings from a long-term follow-up study

Background: The overall survival rate of prostate cancer (PCa) has improved over the past decades. However, huge socioeconomic and racial disparities in overall and prostate cancer-specific mortality exist. The neighborhood-level factors including socioeconomic disadvantage and lack of access to care may contribute to disparities in cancer mortality. This study examines the impact of neighborhood deprivation on mortality among PCa survivors. Methods: North Carolina–Louisiana Prostate Cancer Project (PCaP) data were used. A total of 2113 men, 1046 AA and 1067 EA, with PCa were included in the analysis. Neighborhood deprivation was measured by the Area Deprivation Index (ADI) at the census block group level using data from the US Census Bureau. Quintiles of ADI were created. Cox proportional hazards and competing risk models with mixed effects were performed to estimate the effect of neighborhood deprivation on all-cause and PCa-specific mortality adjusted for age, race, study site, insurance status, and comorbidities. Results: Participants living in the most deprived neighborhoods had an increased risk for all-cause mortality (quintiles 4 + 5: adjusted hazard ratio [aHR] = 1.51, 95% confidence interval [CI] = 1.16–1.96) compared to those in the least deprived (quintile 1) neighborhoods. The risk of prostate cancer-specific mortality was also higher among those living in the deprived neighborhoods (quintiles 4 + 5: aHR = 1.90, 95% CI = 1.10–3.50) than those in the least deprived neighborhood. Conclusions: The findings suggest neighborhood-level resources or health interventions are essential to improve survival among men with PCa. Additional research should focus on the mechanisms of how the neighborhood environment affects mortality

Human conjunctiva organoids to study ocular surface homeostasis and disease

The conjunctival epithelium covering the eye contains two main cell types: mucus-producing goblet cells and water-secreting keratinocytes, which present mucins on their apical surface. Here, we describe long-term expanding organoids and air-liquid interface representing mouse and human conjunctiva. A single-cell RNA expression atlas of primary and cultured human conjunctiva reveals that keratinocytes express multiple antimicrobial peptides and identifies conjunctival tuft cells. IL-4/-13 exposure increases goblet and tuft cell differentiation and drastically modifies the conjunctiva secretome. Human NGFR+ basal cells are identified as bipotent conjunctiva stem cells. Conjunctival cultures can be infected by herpes simplex virus 1 (HSV1), human adenovirus 8 (hAdV8), and SARS-CoV-2. HSV1 infection was reversed by acyclovir addition, whereas hAdV8 infection, which lacks an approved drug therapy, was inhibited by cidofovir. We document transcriptional programs induced by HSV1 and hAdV8. Finally, conjunctival organoids can be transplanted. Together, human conjunctiva organoid cultures enable the study of conjunctival (patho)-physiology.</p

Feasibility of Gold Fiducial Markers as a Surrogate for Gross Tumor Volume Position in Image-Guided Radiation Therapy of Rectal Cancer

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Gravitational radiation from gamma-ray bursts as observational opportunities for LIGO and VIRGO

Gamma-ray bursts are believed to originate in core-collapse of massive stars. This produces an active nucleus containing a rapidly rotating Kerr black hole surrounded by a uniformly magnetized torus represented by two counter-oriented current rings. We quantify black hole spin-interactions with the torus and charged particles along open magnetic flux-tubes subtended by the event horizon. A major output of Egw=4e53 erg is radiated in gravitational waves of frequency fgw=500 Hz by a quadrupole mass-moment in the torus. Consistent with GRB-SNe, we find (i) Ts=90s (tens of s, Kouveliotou et al. 1993), (ii) aspherical SNe of kinetic energy Esn=2e51 erg (2e51 erg in SN1998bw, Hoeflich et al. 1999) and (iii) GRB-energies Egamma=2e50 erg (3e50erg in Frail et al. 2001). GRB-SNe occur perhaps about once a year within D=100Mpc. Correlating LIGO/Virgo detectors enables searches for nearby events and their spectral closure density 6e-9 around 250Hz in the stochastic background radiation in gravitational waves. At current sensitivity, LIGO-Hanford may place an upper bound around 150MSolar in GRB030329. Detection of Egw thus provides a method for identifying Kerr black holes by calorimetry.Comment: to appear in PRD, 49

In vitro 3D phenotypic drug screen identifies celastrol as an effective in vivo inhibitor of polycystic kidney disease

Polycystic kidney disease (PKD) is a prevalent genetic disorder, characterized by the formation of kidney cysts that progressively lead to kidney failure. The currently available drug tolvaptan is not well tolerated by all patients and there remains a strong need for alternative treatments. The signaling rewiring in PKD that drives cyst formation is highly complex and not fully understood. As a consequence, the effects of drugs are sometimes difficult to predict. We previously established a high throughput microscopy phenotypic screening method for quantitative assessment of renal cyst growth. Here, we applied this 3D cyst growth phenotypic assay and screened 2320 small drug-like molecules, including approved drugs. We identified 81 active molecules that inhibit cyst growth. Multi-parametric phenotypic profiling of the effects on 3D cultured cysts discriminated molecules that showed preferred pharmacological effects above genuine toxicological properties. Celastrol, a triterpenoid from Tripterygium Wilfordii, was identified as a potent inhibitor of cyst growth in vitro. In an in vivo iKspCre-Pkd1lox,lox mouse model for PKD, celastrol inhibited the growth of renal cysts and maintained kidney function.Medicinal Chemistr